Regional Chemotherapy Is a Valuable Second-Line Approach in Metastatic Esophageal Cancer after Failure to First-Line Palliative Treatment
Round 1
Reviewer 1 Report
In the present study, Vashist and colleagues present a series of 14 patients with metastatic esophageal cancer treated by intraarterial chemotherapy. None of the patients was treatment naiv and they received different types of previous therapies (e.g. chemo, radiation, tumor resection, etc).
The authors revealed a remarkable OS of 38 for the entire patients cohort.
This report is the first of a series of esophageal cancer and intraartieral chemotherapy and despite a rather small case series, the outcome is worth to be reported.
I have some minor aspects to be addressed:
- How were the chemo agents chosen for which patient? The applied chemotherapeutics are not standard in the treatment of EC in systemic therapy
- The aspect of local focussed chemotherapy in systemic metastasized patients is not clear to me. Some patients suffered from brain metastasis, why should there be a benefit from intraabdominal chemotherapy with a highly morbidity and invasive technique. Wouldn't this therapy be much better suited for local tumor stages?
Same with bone metastasis. These metastatic pattern demonstrate a real systemic disease, should there not be systemic therapies be applied?
Author Response
Dear Reviewer, many thanks for the positive remarks regarding our study. We have been able to respond to all of your minor remarks - hope they are convincing and satisfying.
Best regards
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This is a small series of 14 patients who underwent regional chemotherapy for metastatic esophageal cancer in a palliative setting in a single center. The authors could show the feasibility of such treatment. In addition, the related morbidity was acceptable, and the oncological results superior to other second-line palliative treatment.
As the procedure is technically demanding and only few patients do qualify, the experience of the surgical and oncological community is rare.
Criticisms
- In the introduction section, the authors should reconsider whether all of their papers must be cited (inappropriate self-citation, ref 14-19).
- Clear inclusion and exclusion criteria should be added, to get a better understanding, which patients would benefit from such an invasive treatment.
- The choose of the used chemotherapeutic drugs should be justified and explained.
- Some information on the intraoperative difficulties should be added.
- Are the three used types of regional perfusion therapy comparable, and could they presented separately or just together as one treatment entity.
- How many treatment cycles are optimal? Can it be used as long-term maintenance therapy?
- How long was the inclusion period for this study? The authors mentioned “a long inclusion period” in the discussion.
please check the references, i.e. ref 21.
Author Response
This is a small series of 14 patients who underwent regional chemotherapy for metastatic esophageal cancer in a palliative setting in a single center. The authors could show the feasibility of such treatment. In addition, the related morbidity was acceptable, and the oncological results superior to other second-line palliative treatment.
As the procedure is technically demanding and only few patients do qualify, the experience of the surgical and oncological community is rare.
Reply: We thank reviewer 2 for his acknowledgement.
Criticisms
- In the introduction section, the authors should reconsider whether all of their papers must be cited (inappropriate self-citation, ref 14-19).
Reply: We agree that self-citations should be used within limits but since the described perfusion techniques have been developed at our centre and we are carrying out the highest numbers of such perfusions globally, literature from other authors are very limited. However, whenever another author / centre has been available – we did also cite them (see Guadagni and Laface).
- Clear inclusion and exclusion criteria should be added, to get a better understanding, which patients would benefit from such an invasive treatment.
Reply: Regional chemotherapy can be administered in several manners since a number of infusion and perfusion techniques are available. In addition, the morbidity and mortality of regional chemotherapy is extremely low. We had no grade 3 or 4 haematological complication. The option to perform a chemo-filtration along with infusion and perfusion techniques further adds to the possibility of application of this approach in otherwise severely impaired patients. We have stated that most of our patients even had ECOG 2 or 3. For such patients otherwise no treatment option is applicable. We have added few lines in the method section – page 4 – yellow highlighted.
- The choose of the used chemotherapeutic drugs should be justified and explained.
Reply: It is an excellent remark and the selection mainly is based on experience and the limited data available. Unfortunately, data on this issue is scare. We have added a line to the Method section – Cytotoxic drugs page 6 and 7 – yellow highlighted. The reference has been added too. Experimental in-vitro cell culture studies have demonstrated that mitomycin C and doxorubicin have increased cell toxicity under hypoxic conditions and cisplatin has equal cell toxicity under aerobic and hypoxic conditions (Teicher BA, Lazo JS, Sartorelli AC (1981) Classification of Antineo- plastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res 41:73–81)
- Some information on the intraoperative difficulties should be added.
Reply: In this series no intraoperative events appeared. It is true many complications can potentially appear but to list and elaborate on those within the frame of this small series would be not suitable. We are currently preparing a manuscript on the technical features of perfusion techniques that will include such issues.
- Are the three used types of regional perfusion therapy comparable, and could they presented separately or just together as one treatment entity.
Reply: The various techniques can only be applied sequentially – means isolated thoracic perfusion is not combined along with upper abdominal perfusion. However, in case of upper abdominal perfusion an additional angiographic catheter can be placed in the hepatic artery for example and part of the chemotherapy directly injected in the hepatic artery followed by an upper abdominal perfusion. Also, in patients in whom severe tumor necrosis is an issue an arterial infusion can be performed prior to a perfusion therapy. In total many combinations are possible – however regional chemotherapy focuses on a limited region. Please also see our remarks above for reviewer 1 to a similar question and our method section on techniques.
- How many treatment cycles are optimal? Can it be used as long-term maintenance therapy?
Reply: Potentially unlimited number of cycles can be carried out. As demonstrated in figure 2 the best response is seen after 3 cycles. Infusion techniques can be certainly used as a long-term therapy. For perfusion therapy a direct access to semi-large vessels is mandatory but we have patients (not in this series) where perfusions have been caried out upto 9 times.
- How long was the inclusion period for this study? The authors mentioned “a long inclusion period” in the discussion.
Reply: Inclusion period lasted from 2002 – 2019. We have added that information in the method section. Page 4
please check the references, i.e. ref 21.
Reply: It is a manually generated reference - a book chapter.
Author Response File: 
Author Response.docx
